YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA737794 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14816700.fastq.gz | Fastqsanger.gz | |||
| SRR14816689.fastq.gz | Fastqsanger.gz | |||
| SRR14816690.fastq.gz | Fastqsanger.gz | |||
| SRR14816691.fastq.gz | Fastqsanger.gz | |||
| SRR14816692.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 36 |
Similar Datasets
Project description:Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone posttranslational modification, how oncogenic signaling remodels DNA methylation remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancer. Here we identify the 5-methylcytosine dioxygenase TET1 as a direct YAP target and a master regulator that coordinates the genome-wide epigenetic and transcriptional reprogramming of YAP target genes in the liver. YAP activation induces the expression of TET1, which physically interacts with TEAD to cause regional DNA demethylation, histone H3K27 acetylation and chromatin opening in YAP target genes to facilitate transcriptional activation. Loss of TET1 not only reverses YAP-induced epigenetic and transcriptional changes but also suppresses YAP-induced hepatomegaly and tumorigenesis. These findings exemplify how oncogenic signaling regulates site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and diseases.
2022-05-09 | GSE178227 | GEO
Project description:Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone post-translational modifications, how DNA methylation is remodeled by oncogenic signaling remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancers. Here, we identify the 5-methylcytosine dioxygenase TET1 as a direct YAP target and a master regulator that coordinates the genome-wide epigenetic and transcriptional reprogramming of YAP target genes in the liver. YAP activation induces the expression of TET1, which physically interacts with TEAD to cause regional DNA demethylation, histone H3K27 acetylation and chromatin opening in YAP target genes to facilitate transcriptional activation. Loss of TET1 not only reverses YAP-induced epigenetic and transcriptional changes but also suppresses YAP-induced hepatomegaly and tumorigenesis. These findings exemplify how oncogenic signaling regulates the site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and disease.
| S-EPMC9357225 | biostudies-literature
Project description:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease. We report genome-wide 5hmC enrichment profiles and RNA-Seq gene expression in MLL-AF9 transformed and control mouse bone marrow mononuclear cells. These 5hmC profiles are derived from selctive chemical labeling and enrichment of 5hmC containing genomic DNA fragments, while the RNA-Seq expression profiles are generated from polyA enriched RNA
2015-12-14 | E-GEOD-42990 | biostudies-arrayexpress
Project description:Ovarian cancer (OV) is the leading cause of mortality from gynaecological malignancies with poor prognosis and limited therapeutic options. Prevalent copy number alteration (CNA) is a genetic characteristic of OV, but its contribution to tumorigenesis remain unclear. Here, we identify RAD21, a component of the cohesin complex, as a frequently amplified and overexpressed oncogene in high grade serous ovarian cancer (HGSOC), the most common subtype of OV. RAD21 copy number amplification and overexpression are correlated with poor prognosis in HGSOC. In HGSOC cells and xenograft models, depletion of RAD21 inhibited cell proliferation by inducing mitotic phase arrest and thereby reducing tumour growth, whereas overexpression of RAD21 conferred resistance to carboplatin. Mechanistically, we found that RAD21 interacts with YAP/TEAD4 transcriptional co-repressors and recruits NuRD complex to suppress the downstream targets. Additionally, genetic and pharmacologic inhibition of YAP disrupts the co-repressor complex to suppress the oncogenic activity of RAD21 and recapitulates the phenotypes of RAD21 depletion in HGSOC. Therefore, our work sheds light on the oncogenic role of frequent CNAs and identifies a previously unrecognized role of RAD21/YAP complex which contributes to tumorigenesis and chemo-resistance in HGSOC.
2023-04-10 | GSE156845 | GEO
Project description:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
2015-12-14 | GSE42990 | GEO
Project description:YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A mediated-mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.
2018-05-23 | MSV000082392 | MassIVE
Project description:YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A mediated-mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.
2018-05-23 | MSV000082393 | MassIVE
Project description:Oncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis is not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting DNA demethylase TET oncogene family member 1 (TET1) via the C/EBPα transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression via active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in a majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors, which may have therapeutic benefit for oncogenic EGFR-mediated lung cancers and glioblastomas. HCC827-Del (EGFR L747-S752) and HCC827-Del-TM (EGFR L747-S752/T790M) cell lines were treated with Decitibine (2.5 μM) and Vorinostat (1μM) or as a control cells that were treated with DMSO for 72 hrs. Expression profiling was performed using 3 biological replicates for each condition for a total of 12 samples analyzed.
2016-06-23 | E-GEOD-39292 | biostudies-arrayexpress
Project description:Oncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis is not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting DNA demethylase TET oncogene family member 1 (TET1) via the C/EBPα transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression via active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in a majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors, which may have therapeutic benefit for oncogenic EGFR-mediated lung cancers and glioblastomas.
2016-06-23 | GSE39292 | GEO
Project description:The Hippo-YAP signaling pathway has emerged as a major driver of tumorigenesis in a wide spectrum of human cancers. YAP functions as a transcriptional activator and while details of YAP regulation are emerging at a fast pace, it remains unknown what downstream targets are critical for YAP oncogenic functions. To establish the mechanisms involved and identify disease-relevant targets we examined the role of YAP in neurofibromatosis type 2 (NF2) using cell and animal models. YAP function is required in NF2-null Schwann cells to promote cell survival and for tumor growth, in vivo. Moreover, YAP promotes transcription of several targets including Prostaglandin-endoperoxide synthase 2 (PTGS2), which controls production of prostaglandin E2 (PGE2) and amphiregulin (AREG), a member of the epidermal growth factor family. Both AREG and PGE2 converge to activate survival signaling through EGFR, in a Src-dependent manner, thus promoting cell survival. Importantly, treatment with the COX2 inhibitor celecoxib significantly repressed the growth of NF2-null Schwann cells in vitro and tumor growth in a mouse model of NF2-associated schwnnoma.
2016-04-30 | GSE61528 | GEO